Most current chemotherapeutics have non-specific mechanisms of action and poor biodistribution profiles which result in dose-limiting toxicities tha prevent optimal efficacy from being obtained. Ribonucleic acid interference (RNAi) has the potential to be a safe, selective and personalized treatment approached for a variety of genetic-based diseases, including cancer. In particular, the design of small interfering RNA (siRNA) sequences to prevent the expression of cancer-fueling mutations provides an alternative to current therapeutic approaches. However, an effective delivery vehicle is required for systemic RNAi therapy to protect siRNA during circulation, concentrate siRNA at tumor sites and mediate cellular uptake as well as endosomal escape. This project is designed to optimize a novel, combinatorial RNAi treatment for advanced breast cancer based on delivery by calcium phosphate nanoparticles, called NanoJackets. Building on the demonstrated in vivo efficacy of an untargeted siRNA NanoJacket prototype, an active targeting ligand will be added and evaluated for improved biodistribution, cellular uptake and in vivo efficacy of siRNA NanoJackets for breast cancer therapy. If successful, the development of this targeted, combinatorial RNAi nano-therapeutic will provide a novel option for the personalized treatment of breast cancers that fail to respond to current therapies.